Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation

• Published in: Scientific reports Vol. 5; no. 1; p. 16577
• Main Authors: Lee, Sun Joo, Jeong, Ji Yun, Oh, Chang Joo, Park, Sungmi, Kim, Joon-Young, Kim, Han-Jong, Doo Kim, Nam, Choi, Young-Keun, Do, Ji-Yeon, Go, Younghoon, Ha, Chae-Myeong, Choi, Je-Yong, Huh, Seung, Ho Jeoung, Nam, Lee, Ki-Up, Choi, Hueng-Sik, Wang, Yu, Park, Keun-Gyu, Harris, Robert A., Lee, In-Kyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.11.2015; Nature Publishing Group
• Subjects: 13/109; 13/2; 13/51; 14/19; 14/34; 42/70; 42/89; 631/80/304; 692/4019/592/2193; Animals; Aorta; Apoptosis; Apoptosis - genetics; Arteriosclerosis; Biomarkers; Bone growth; Bone morphogenetic protein 2; Bone Remodeling - genetics; Calcification; Calcification (ectopic); Calcium homeostasis; Calcium phosphates; Cardiovascular diseases; Cell Differentiation; Cells, Cultured; Dehydrogenase; Dehydrogenases; Disease Models, Animal; Gene Expression; Gene Knockdown Techniques; Homeostasis; Humanities and Social Sciences; Humans; Male; Mice; Mice, Knockout; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Morbidity; multidisciplinary; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; Osteogenesis; Osteogenesis - genetics; Phosphorylation; Protein Binding; Protein Kinase Inhibitors - pharmacology; Protein Kinases - chemistry; Protein Kinases - genetics; Protein Kinases - metabolism; Pyruvate dehydrogenase (lipoamide); Pyruvic acid; Rodents; Science; Smad1 Protein - metabolism; Smad5 Protein - metabolism; Smad8 Protein - metabolism; Smooth muscle; Vascular Calcification - metabolism; Vitamin D3
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep16577

Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D 3 -treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification.